Abstract

Tissue resident memory (TRM) T cells persist in human genital mucosa long after healing of herpes simplex virus 2 (HSV-2) infection. These TRM T cells provide effective protection to rapidly contain reactivating viruses before clinical manifestation occurs, making them excellent candidates for developing novel approaches to controlling HSV2 reactivation. To understand the dynamics of TCR repertoire and the kinetics of T cell clones during disease resolution, sequential biopsies were obtained in three individuals at the time of active lesions and 2, 4, 8 weeks post-healing, and were subjected to high-throughput sequencing of the TCRβ chain hypervariable CDR3 region. Oligoclonal immune profiles were evidenced in all biopsy tissues with a few TCR sequences constituting 30–40% of the TCR repertoire. The usage pattern of various TCRVB genes was similar among tissues of active lesion and post healed biopsies of the same subject. However, the TCRVB usage differed dramatically between the TCR repertoire in tissues and those of PBMC derived HSV-2 specific T cells taken at the same time point within each individual. This difference was more extreme when evaluating the TCR sequences that selectively persisted in post-healing biopsies. The top ten predominant TCR sequences persisting in tissues during clinical quiescence 4–8 weeks post healing did not overlap with HSV-2 specific T cells isolated from PBMC. These data suggest a TCR intrinsic property might dictate the TRM repertoire, and that the antigen specificity of TRM might differ considerably from circulating HSV-2 specific T cells.